In a eukaryotic cell, genes are transcribed into messenger RNAs (mRNAs), and mRNAs are translated into proteins. When this process goes awry, cells may die or become cancerous. Upon disease onset, these catastrophic events are extremely hard to detect because of the clinician's inability to detect a single abhorrent cell or group of cells. Instead, disease is generally detected on the macroscale, resulting in large numbers of cancer cells that have to be surgically removed or killed by radiation or chemotherapeutic drugs. Moving from this macroscale therapeutic approach requires novel technologies, many of which are still being developed.
Although molecular therapy has made significant progress in the development of gene delivery systems that can change the genetic makeup of cells, and chemotherapeutic drugs have been engineered to be more specific in their effect on cell death, advances still need to be accomplished in all therapeutic systems that require the delivery of active biomolecules. Medical researchers continue to search for a reliable way to pinpoint drug delivery to specific cells, and many laboratories are relying on biochemical properties to help fabricate these therapeutic delivery systems. By targeting a specific cell surface characteristic, it may be possible to identify an individual cell population on the microscale instead of groups of cells or tissues on the macroscale. This targeting should provide an avenue for highly specific drug delivery. Encapsulation processes should increase half-lives of therapeutic agents and protect them from the immune-based degradation machinery that detects non-self contaminants. Delivery and encapsulation are intimately coupled because once the therapeutic agent has been encapsulated, delivery must occur for the action mechanism selected. Giving the therapeutic agent a way to be both encapsulated and possess its own address for delivery requires biological, chemical and physical design principles. Organic recognition elements (typically antibodies generated against a protein present on the target cell's surface or short peptides that also recognize cell surface proteins) have to be generated and attached to the surface to produce a biosignature, and genetic and drug therapeutic agents have to be physically incorporated into the delivery system.
The introduction of nanoparticles to this process provides at least three desired characteristics to a proposed delivery system, namely: 1) the correct length scale for biomolecular interactions, 2) physical support and 3) means of chemical attachment. Nanoparticles can be produced with very small diameters (<100 nm) and out of a variety of compositions, such as metals, metal oxides, metal non-oxides, and polymers, and they can be functionalized to behave as molecular linkers. Nanoparticles have physical, chemical and electronic properties uniquely different from those of single molecules and bulk materials. Because of their unique properties, there is a great research effort in trying to harness these properties to prepare medical devices utilizing nanoparticles. The synthesis of diverse nanoparticle species with different functional groups that allow needs-based designer modifications may be the next critical ingredient in gene therapy and imaging systems.
Significant progress has been made in the ability to deliver genetic therapeutics and chemotherapeutics to cells or groups of cells, but encapsulating the dual functions of payload and delivery have not been achieved. One of these techniques, liposome-mediated delivery, provides a therapeutic molecule with an encapsulating lipid bilayer. This method provides wide applicability to deliver different therapeutic molecules like proteins, peptides, and nucleic acids, making this delivery choice very attractive. Liposomal spheres are generated by mixing a drug-containing aqueous mixture with lipids, and creating spheres by nebulization or high speed vortexing resulting in both nanospheres and microspheres. The size of the sphere dictates the amount of therapeutic agent delivered. Researchers have created a size range of 5-500 micron uniform spherical droplets, and one research group has shown that the release rate depends on the size of the therapeutic-containing sphere1. This observation led to creating a nebulizer device that generates a range of sphere sizes simultaneously, providing time-released delivery of therapeutic agents, first from small spheres and then from large spheres2. However, severe obstacles faced are their lack of robustness3, and the inherent difficulty of keeping lipid bilayers in micellar (spherical) form4. Other practical technical problems also plague this delivery system, namely:                1. The liposomal spheres have an extremely high polydispersity index, thus specificity is compromised at the first synthesis step.        2. It is hard to functionalize both the interior and exterior of liposomes.        3. There is a low therapeutic payload with respect to liposome size.        4. It has been difficult to target delivery to a specific cell type.        
Liposomes circulate in the blood for long periods of time often evading detection by the body's immune system, enhancing the likelihood that the encapsulated drug will be delivered to its target, therefore mitigating harsh cytotoxicity coincident with many therapeutic treatments. In spite of these advantages, only three liposome-mediated drug delivery systems have overcome the barriers presented by the available methodologies and entered the drug market: doxorubicin, daunorubicin, and amphotericin B.
An alternative method for therapeutic delivery has been what some people refer to as nanomedicine5. An example of nanomedicine is nanoshells, hollow spheres made of silica nanoparticles and coated with gold nanoparticles6. Because of their extraordinarily small size (˜10 nm), these spheres are embedded IN a matrix polymer and injected into the body7. It is thought that after heating with an infrared laser, the energy released from the nanoshells will make the polymer melt and release their drug payload at a specific site6. However, because they are on the nanoscale, it is hard to incorporate dual functionality into these nanoparticles themselves or produce them to be a self-delivery system; the polymer is required for encapsulation and thus obviates some of the benefits of producing nanosized molecules.
In contrast to silica nanospheres decorated with gold, bucky balls, carbon fullerenes, are also being tested as possible candidates for chemotherapeutic delivery8. Antibodies have been successfully attached to bucky balls9, and bucky balls have also been decorated with antiviral agents10. However, several shortcomings compromise this drug delivery system:                1. Fullerenes are organic, thus not readily soluble in the aqueous phase where many biological interactions occur.        2. It is hard to disperse fullerenes in the blood because of poor mixing due to solubility.        3. The organic molecular environment in unfavorable to an antibody/antigen interaction, whereas the delivery system is dependent on this interaction occurring.        4. Functionalization of buckyballs occurs solely on the exterior, thus it is difficult to synthesize dual-function buckyballs, thereby restricting biochemical recognition.        
The typical route chosen by chemists and materials scientists to assemble nanoparticles is to utilize and exploit specific biomolecular recognition, such as the complementarity of DNA nucleotides or enzyme substrate pairs11, but dual-functionality is not accomplished. Gold nanoparticles have been bound to DNA TO form reversible aggregates12, and gold particles have been successfully aggregated even in the shape of spheres approaching the microscale13. Dimers of cadmium selenide (CdSe) nanoparticles have been synthesized using bis(acyl hydrazide). Antigen-antibody interactions have also been utilized to assemble gold nanoparticles.14 However, the use of DNA hybridization, protein substrate, or antibody/antigen interactions have not facilitated a single step, ‘one-pot’ synthesis of macroscopically phase-separated materials from nanoparticles, such as the hollow spheres presented in the present application.
Hollow spheres are an extremely attractive structural motif for many applications due to their encapsulation properties, and their preparation in the sub-micron diameter range has been an active area of materials chemistry15. In a typical procedure, large particles (submicron/micron diameters ˜100's of nm) are coated with a ceramic (or polymer) precursor, and then the particle is removed to leave behind a ceramic (or polymer) shell. The size of the hollow sphere is controlled by the templating particle, the thickness of the shell is controlled by the deposition process, and the composition of the shell is determined by choice of precursor. Interesting variations include using gold nanoparticles to template polymer shells16, and using polymer microspheres to template polyelectrolyte shells layer-by-layer and titania shells17. In a different approach, a polymer cast of an opaline structure of silica microspheres was created, the silica was removed and a ceramic precursor was deposited onto the interior polymer walls to construct titania hollow spheres18. While such preparation routes to hollow spheres appear quite flexible, they are a labor-intensive process, requiring multiple steps to be done in a sequential manner. Encapsulation of a desired compound within the hollow spheres is even more difficult to accomplish because the spheres can not be formed, dissociated (to allow agent incorporation) and reformed in physiological relevant synthesis conditions to protect from degradation of the desired compound which is usually a therapeutic agent.